South Africa (SA) has the largest number of HIV infections in the world. Although initial reports suggested that rates of ART adherence in sub-Saharan Africa were high, recent data indicate that adherence may be a major obstacle to actualizing the full benefits of ART. Inadequate adherence and associated drug resistance are factors contributing to high rates of treatment failure often observed within the first 12 months of ART initiation. Patient understanding of HIV disease and the necessity for high ART adherence, as well as the social support for maintenance of adherence are key to the long-term success of ART. Given the ratio of physicians/nurses to patients, ART adherence counseling in SA is conducted mostly by lay counselors with varied expertise and skills, and minimal supervision. Lack of standardization and variability in quality of counseling has prompted urgent calls for an effective adherence intervention that can be delivered by trained lay staff (with fidelity) to establish optimal adherence among patients initiating ART. With the support of an NIMH R34 grant, we developed Masivukeni, an innovative, multi-media computer-based intervention developed by our US-SA research team with SA patients and care providers using community based participatory research methods. Based on Social Action Theory, Masivukeni addresses contextual factors that may promote or impede adherence, and self-regulation and social support factors that can improve behavioral and biological outcomes. The utilization of computer-based technology by counselors working with patients and their treatment support partners enables lay counselors with minimal training and supervision to teach complex medical information and problem-solving skills, with culturally relevant, interactive imagery. The intervention also enhances counselor capacity for screening and making referrals for mental health and substance use problems among patients initiating ART. Our pilot study demonstrated high acceptability and feasibility, as well as promising effects on key primary and secondary outcomes. Through a collaboration among City and Provincial DOHs in Cape Town, research and clinical partners in SA (University of Cape Town) and the US (HIV Center for Clinical and Behavioral Studies at NYS Psychiatric Institute/RFMH and CCNMTL at Columbia University), we propose to compare Masivukeni to standard care by randomly assigning 360 patients initiating ART to one of the two study conditions in two publicly financed medical clinics serving predominantly poor communities with high HIV prevalence. Patients will be followed over the course of one year. Assessments will be administered to patients at baseline, 6 months and 12 months post baseline. Through partnership with clinicians and DOH policy-makers, the intervention will be quickly available for wide-scale dissemination if shown to be efficacious. Further, an efficacious intervention of this modality could readily be culturally tailored and implemented in other regions of the world, including the US where long-term adherence remains a challenge, particularly for patients with low literacy and mental health and substance use problems.